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Mission Impossible Mission Impossible Company LimitedCompany Limited
Ms.Sathaporn Prutipanlai Ms.Waraporn Parnlob Ms.Wang Don Mei Ms.Siranee Srisai Mr.Kanatip Rathanachoo Ms.Thida Chanyachukul
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Introduction Ritonavir synthesis / Purification Simulation design of production plant Production plant cost analysis Pollution control strategies Plant location and quality control Conclusions and recommendations
Presentation OutlinePresentation Outline
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Production processProduction process
Production can be divided into upstream processing
the initial fermentation process, which results in the initial generation of
product
downstream processing
the actual purification of the product and
generation of finished product format
followed by sealing of the final product
containers
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Types of drug designTypes of drug design
- Non hydrolyzable analog of pepti de substrate
- Transition state analogs - Pepstatin protease complex - Two fold symmetrical or pseudos
ymmetrical inhibitor - Structure based inhibitor
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Factors that influence drug Factors that influence drug designdesign
Pharmacokinetics high oral bioavailability low hepatic clearance
Pharmacodynamics Interaction between drugs and HI
V protease enzyme hydrophobic interaction
low toxicity
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HIV Protease HIV Protease enzymeenzyme
One type of aspartic acid enzyme Each monomeric contributes a conserved catalytic triad Protease’ s function exists as a C
2- symmetry homodimer
works as a homodimer that cleaves
gag/pol polypeptide of HIV
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CC22 symmetry development symmetry development
Peptidomimetic Substrate C
2 symmetry
1 st Imposition of an axis of symmetry on the peptide functionality in the substrate
2 nd - Arbitrary deletion of either the N terminal or -C terminal
3 rd C2
symmetry operation is applied to the remaining
portion to generate a symmetric core unit
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Ritonavir synthesisRitonavir synthesis + VCl 3 /Zn I I I
- a ami noal dehyde I I diols (white solid)
bromoacetate(whitesol i d)
cyclization hydrolysis I V
hydrolysis reduction
diamine (white solid) VI compound X (white solid) V epoxide(whitesolid)
VI I
acylation VI I I IX coupling resin compound compound XXXIIIa
Ritonavir
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Purification of RitonavirPurification of Ritonavir + II chromatograp
hy - a aminoaldehyde diols (white solid) III
bromoacetate (white solid)
pricipitation filtration IV
chromatography filtration VI V
diamine (white solid) compound X (white solid) epoxide (white solid)
VII distillation chromatography
resin compound VIII compound XXXIIIa IX Ritonavir
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Polishing steps of RitonavirPolishing steps of Ritonavir
distillation
filtration
final product dryer
formulation
crystallization
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Design consideration
Production quantity ~ 82,763 kg/yr
Batch mode
Operating time = 7,920 h/yr
Plant batch time = 23 h
270Numberof batches peryear=
Production Rate = 307 Kg/Batch
9Composed of major reactions
43SuperPro Designer Version .
Simulation Design of the Simulation Design of the PlantPlant
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P-4 / V-102Batch Distillation
P-8 / DDR-101Drum Drying
waste
S-108Reagent A
Reagent B
S-105S-106
Product
Purification SectionReaction Section
P-3 / UF-101Ultrafiltration
S-110
S-111
S-115
S-116
S-107
S-109S-114
P-6 / MSX-101Mixer-Settler Extraction
P-7 / C-101Gel Filtration
P-1 / MX-101Mixing
P-2 / V-101Vessel Procedure
P-5 / DF-101Diafiltration
Reagent C
S-112
Conceptual Design of the Conceptual Design of the PlantPlant
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P-2 / V-101Vessel Procedure
P-3 / MX-101Mixing
N(((benzyl...
triethylamine
w/re3w/re4
feed for P3
water1
citric
w/re1w/re2
P-4 / OS-101Organic Separation
feed for P4
w/re5
close
oxalyl chloride
P-5 / UF-101Ultrafiltration
P-6 / DDR-101Drum Drying
w/re6
feed for P6w/re7
Feed for P7
feed for P5
DMSO
feed for P-2
P-1 / HX-101Cooling
Protease Inhibitor Production Protease Inhibitor Production PlantPlant
Reaction 1
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Plant Cost AnalysisPlant Cost Analysis
Total Capital Investment : $ 120 M
Annual Operating Cost : $ 192 M
Unit Production Cost : $ 2,301/kg
ROI at the current market price:
700.76 %
Payback Time : 0.14 year
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Reaction 1 has the most expensive operation cost
Reaction 3 has the highest fixed cost
Optimum production capacity is 309 kg/batch
Unit production cost: $2,301/kg or $1.4/pill
Current selling price : $11.5/pill or $23/day
Plant Cost Analysis Plant Cost Analysis SummarySummary
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Change payback time to 6 years
Return of investment : 16.67 %
Selling price can be reduced by 7 times
Cost $ 3.24 per patient per day
(instead of $ 23)
Mission Impossible Mission Impossible ObjectivesObjectives
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Pollution Control Pollution Control StrategiesStrategies
Environmental Regulation Authorities
Ministry of Industry Ministry of Science, Technology
and Environment Ministry of Interior Ministry of Public Health
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1992Factory Act,
Pharmaceutical Industry :- 46Classified in category- iiiiiiii i iiii ii iiiiiii3:
i iiiiii iiiii ii iii iiiiiiiiii
Pollution Control Pollution Control StrategiesStrategies
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Total waste produced : 39 points
(all reactions)
14765890Liquid Waste : , , kg/yr : 8 , 9 5 8 ,9 5 4 / i iiii i ii :
Pollution Control Strateg Pollution Control Strategiesies
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P-1 / MX-101
MixingP-2 / AB-101
Aerobic BioOxidation
P-3 / CL-101
Clarification
P-4 / GMF-101
GM Filtration
P-5 / BF-101
Belt Filtration
P-6 / SLDR-101
Sludge Drying
InfluentS-102
P-7 / MX-102
Mixing
S-104
S-105
S-106
S-108
Effluent
S-101
S-111
AEB-Emission
S-113
S-114
Air In
Final Sludge
Air Out
S-107
S-103
Lime
Clrf-Emission
Wastewater Treatment Wastewater Treatment PlantPlant
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Plant Plant locationlocation
Industrial estate in Eastern Seaboard major structures proper infrastructures privilege in taxation enough labor / cheap wage rate
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Quality controlQuality control
Manufacturing process on Quality Raw material In process Finishing product Labels Packaging material
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Conclusions
Successfully designed a production plant Composed of 9 major reactions Effective and economic purification
methods should be employed to get the desired product
Environmental strategies have to be set-up
Industrial estate in Eastern seaboard is chosen
QC for each production step
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83546 309 270Produce , kg/yr( kg/batch) at batches/yr 7At present market price, we make profit of
0076. % (ROI) iiiii iii ii iiiiiii ii i iii ii 7
324(cost of . $ per patient per day) Sensitivity analysis was performed
Conclusions
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RecommendatiRecommendationsons
Optimization of synthesis pathway Modify the unit operations esp. purificat
ion for achieving desired product with c-ost effectiveness
Identify the realistic thermodynamic data
Scale the plant down in order to optimiz e the actual market demand of Marketin g group
Simulate using Thailand condition and price
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iiiiiii i iiii iiiiiii iii i iiii iiiiiii iiiiii iiiiiiiii iiiiiii iiiiiii Specify the plant location Develop QC chart
RecommendatiRecommendationsons